Project Summary From persistent infection to cancer, the ability to modulate T cell responses to alleviate disease has become critical. One such type of intervention, immunotherapy (or checkpoint inhibition), is a relatively recent treatment for some cancers and relies on the ability to enhance cancer-specific T cell responses. The mechanisms underlying several of these treatments were discovered using mice persistently infected with lymphocytic choriomeningitis virus (LCMV). As with certain cancers, negative immune regulators (NIRs, e.g. PD-1, IL-10) are upregulated in LCMV infected mice, leading to a hypofunctional, exhausted T cell response and failure to clear the viral infection. Blocking these NIRs relieve T cell exhaustion and lead to viral clearance. We recently discovered that type-I interferons (IFN-I), specifically IFN-?, are the master regulators of NIRs. Blocking IFN-I signaling leads to decreased NIR, increased T cell function, and early viral clearance. While NIR blockade in mice persistently infected with LCMV invariably leads to the reversal of T cell exhaustion and early viral clearance, this is not the case in humans, where only 20-70% of cases respond to immunotherapy. We have identified several strains of mice that die when infected with the same strain and dose of LCMV and by the same route as the persistently infected mice strains used to study the effect of NIRs on T cells. These mice also highly express IFN-I and NIRs but instead of an exhausted T cell response, we observed a robust and immunopathologic T cell response that leads to lysis of infected endothelial cells, vascular permeability and death after 6-9 days of infection. Importantly, we see no differences in viral control (similar viral titers in days 1, 2, 3, and 5) when compared to persistently infected mice, suggesting that early viral dissemination that is critical for establishing a persistent infection is not different between mice that die and those that survive with a persistent LCMV infection. By selective breeding and phenotyping of these two groups of mice, we seek to identify the genetic contributors that control T cell responses despite the presence of negative immune regulators. Once uncovered, these genetic regulators of immune responses may shed light on why some respond the checkpoint therapy while others do not, reveal novel mechanisms controlling T cell function, and lead to novel therapies to alter T cell responses to increase patient survival.